This project is focused on the identification of physiologically critical functions and mechanisms of action of NF-kB transcription factors and their regulators in health and disease. NF-kB is a family of related dimeric transcription factors that serve as primary intracellular mediators during innate and adaptive immune responses. In addition, and importantly, aberrant regulation of NF-kB plays a major role in inflammatory and autoimmune diseases as well as in numerous tumors. It is thus imperative to understand the functions and mechanisms of action of NF-kB factors, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing aberrantly regulated NF-kB in a precisely targeted manner. To identify physiologic roles and mechanisms we make use of mouse models engineered to lack components of the NF-kB transcription factor family or their regulators, as well as models in which the NF-kB factors can be selectively activated. Our work is focused on alternatively and classically activated NF-kB factors, and especially on Bcl-3. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 is an atypical IkB family member that functions as nuclear regulator of NF-kB activity. In FY 2013 we have discovered that Bcl-3 plays a critical role in modulating B cell development. B cells lacking Bcl-3 preferentially develop marginal zone B cells over follicular B cells. Marginal zone B cells serve several innate functions, while follicular B cells are central to adaptive responses. We also demonstrated that Bcl-3 acts cell-autonomously, modulating the process transitional B cells undergo in deciding whether to become a marginal zone or follicular B cells. In FY 2013 we have developed models to assess the role of Bcl-3 in dendritic cells, including a contact hypersensitivity model and a pathogen challenge model. Initial findings point to important functions of Bcl-3 in both contexts. In FY 2013 we have established the T cell transfer model of colitis in order to probe the role of Bcl-3 in pathogenic T cells. To elucidate oncogenic roles of this NF-kB regulator in B cells, we have also developed a model in which Bcl-3 can be specifically activated in B cells together with other NF-kB factors.